Asthma is one of the most common chronic inflammatory diseases, known to affect nearly 25 million citizens in the US alone. In childhood, it is the most common chronic disease, affecting in the region of an estimated 7 million US children.
The pathophysiology of asthma is complex and involves airway inflammation, intermittent airflow obstruction, and bronchial hyper-responsiveness, resulting in shortness of breath, wheezing, coughing, chest tightness and/or pain, as well as other non-specific symptoms in young children, including recurrent bronchitis, bronchiolitis, or pneumonia and the like.
Diagnosis may be made under guidelines from the (US) National Asthma Education and Prevention Program and include prevalence of episodic symptoms of airflow obstruction and/or at least partially reversible airflow obstruction or symptoms, followed by spirometry with post-bronchodilator response, and/or chest radiography (mainly to rule out other pulmonary diseases), as more definitive diagnostic tools.
There is presently no cure for asthma, and treatments often revolve around avoidance of known triggers, such as allergens, dust, pollutants, etc.
In the management and/or treatment of asthma, the ultimate goal is to prevent symptoms, minimize morbidity and prevent functional and psychological morbidity to provide a healthy (or near healthy) lifestyle.
However, there is also a need to treat effectively acute asthma episodes. Such acute exacerbations of asthma are usually commonly referred to as “asthma attacks”. Symptoms include shortness of breath, wheezing, and tightness in the chest. In severe cases, breathing may be significantly impaired such that the condition may become life-threatening.
Acute asthma attacks can often be brought on by infections, allergens, air pollution, exercise or insufficient or inappropriate medication use.
The most commonly-used active agents are presently employed to prevent asthma episodes (“preventers”). Such medications make the airways less sensitive, reduce airway inflammation and help to dry up mucus. Such preventers need to be taken every day to prevent symptoms and asthma attacks, and it may take a few weeks before they reach their full effect. Preventer medications include long-acting bronchodilators, oral theophylline, inhaled corticosteroids, leukotriene modifiers, cromones (cromolyn or nedocromil) and anti-IgE antibodies.
On the other hand, relief medications (“relievers”) are fast acting medications that give quick relief of existing asthma symptoms or “attacks” (wheeze, cough, shortness of breath). They are bronchodilators, which means that they relax the muscle around the outside of the airway, which opens the airway. Every asthmatic patient should have a reliever medication. There are three main categories of reliever medication: theophylline; short-acting beta-agonists, such as terbutaline and salbutamol; and anticholinergics, such as ipratropium.
A more severe condition, known as status asthmaticus or acute severe asthma, is an acute exacerbation of asthma that does not respond well to such standard treatments.
Additionally, there are drawbacks associated with all of the aforementioned drugs (particularly inhaled corticosteroids), including lack of efficacy, non-adherence to treatment regimens, tolerance dependence and safety profiles/side-effects. Accordingly, there is thus a real clinical need for safer and/or more effective treatments of asthma.
Asthmatic bronchoconstriction in humans is mainly caused by mediators activating histamine 1 (H1) receptors (histamine), cysteinyl leukotriene 1 (CysLT1) receptors (leukotrienes C4-D4) and the prostanoid TP receptor (prostaglandin D2 (PGD2), prostaglandin F2α (PGF2α), thromboxane A2 (TXA2); see e.g. Roquet et al, Amer. J. Resp. Crit. Care Med. (1997) 155, 1856-1863 and Beasley et al, J. Appl. Physiol. (1989) 66, 1685-93).
The prostanoid TP receptor has gained much attention as a target for asthma drugs. The TP antagonist seratrodast is available for asthma treatment on the Japanese market (see e.g. Dogne et al, Expert Opin. Investig. Drugs (2002) 11, 275-81).
Asthmatics have been shown to be extremely sensitive to PGF2α when compared to healthy non-asthmatics. It has been suggested that endogenous, locally-formed PGF2α may play an important part in the pathogenesis of asthma (see Mathé et al, Br. Med. J. (1973) 1, 193-96). It is well established that PGF2α contracts human airways by stimulation of the TP receptor (Knight et al, Eur. J. Pharmacol. (1997) 319, 261-267 and Armour et al, Eur. J. Pharmacol. (1989) 165, 215-22).
Pemirolast is an orally-active anti-allergic mast cell inhibitor that is used in the prevention of conditions such as asthma, allergic rhinitis and conjunctivitis. See, for example, U.S. Pat. No. 4,122,274, European Patent Applications EP 316 174 and EP 1 285 921 and Drugs of Today, 28, 29 (1992). The drug is only known for the prophylaxis (i.e. preventative treatment) of asthma, and indeed has been marketed for over 20 years for such use in e.g. Japan as the potassium salt in 5 and 10 mg doses (equating to 4.25 and 8.5 mg of the free acid, respectively) e.g. under the trademark ALEGYSAL™. Two doses are administered every day to provide an immediate mast cell stabilising effect and so the short-term prevention of asthma attacks resulting from subsequent challenge by the aforementioned asthma triggers.
In a paper published in 1989 by Yanagihara et al (see Japan J. Pharmacol., 51, 83 (1989)), studies were performed on pemirolast in an experimental bronchoconstriction model.
Although pre-administration with pemirolast inhibited antigen- and PAF-induced bronchoconstriction in guinea pigs in vivo, pre-treatment of isolated tracheal muscle from guinea pigs with pemirolast at concentrations of 10 μg/mL was found to have no effect on bronchoconstriction (i.e. pre-administration gave rise to no direct bronchodilatory effect on smooth tracheal muscle) when the latter was induced by either leukotriene D4 or PGF2α.
Although much higher concentrations did give rise to some effect, 10 μg/mL equates to a single dose of about 125 mg, which is almost 15 times the clinical dose that is employed in the prophylaxis of asthma.
More significantly, a paper by Ninomiya et al in Japanese Journal of Pharmacology and Therapeutics, 17, 121 (1989) investigated the effect of pemirolast on isolated guinea pig trachea pre-constricted with acetylcholine, histamine, serotonin and barium chloride at higher doses than those presently employed in the clinic. These authors observed potencies of one seventh of that of the well-known, and at that time widely-used, bronchodilator, theophylline, and concluded that the results were not clinically significant.
Accordingly, the conclusion of these studies, and in the art generally (confirmed by Kemp et al in a paper entitled: “Pemirolast, a new oral nonbronchodilator drug for chronic asthma” in Annals of Allergy, 68, 488 (1992) who used twice daily 50 mg doses in humans), is that, when used clinically, pemirolast has no direct bronchodilator activity.
We have found surprisingly that pemirolast is capable of acting as a bronchodilator in human lung tissue, that is, reversing pre-induced bronchoconstriction at concentrations of about 10 μg/mL or higher. We have also found that pemirolast has a previously-undisclosed and unappreciated plasma concentration (exposure) profile which means that it can be employed in doses that are significantly higher than those presently employed in the prevention of asthma, and which are not only safe, but give rise to exposure levels in humans that correspond to those plasma concentrations at which pemirolast appears to be capable of acting, unexpectedly, as a bronchodilator in human patients. Accordingly, at such high doses, pemirolast is potentially of use in the therapeutic treatment of asthma, and in particular in the treatment of acute asthma episodes.